Late-onset and typical Huntington disease families from Crete have distinct genetic origins

HD families in which late-onset occurs consistently in affected members are rare. The objectives of this work was to study such late-onset HD families encountered on Crete, and to trace their genetic origin. Nine late-onset HD kindreds (61 affected members) were studied along with two typical HD families (17 affected members). We genotyped 33 late-onset Cretan HD chromosomes, 9 Cretan typical HD chromosomes and 114 Cretan control chromosomes using 14 STR markers and 20 SNPs that map to 4p16.3. In contrast to the typical HD pedigrees, the late-onset HD families lacked anticipation and juvenile cases. The expanded CAG repeat (36-42 units) in these families remained either stable or it showed small increment instability, even when transmitted through the father. All late-onset HD chromosomes shared a conserved haplotype defined by the markers D4S95: 1090, D4S127: 157, rs362277: A, rs3025814: G, rs2530596: A that span a 0.277-Mb segment on 4p16.3. Coalescence analysis traced this haplotype to a founder who lived about 1000 years ago. In contrast, each of the two typical HD disease pedigrees derived from a different founder. Sequencing of a 5-kb DNA segment immediately upstream of the HD gene revealed a novel single nucleotide polymorphism at -1757 bp relative to the translation start site, which was more prevalent in Cretan than in North American chromosomes. All late-onset HD families on Crete arose from a common founder with the disease's mutation evolving over the centuries via small-increment instability. These findings suggest that cis-acting factors may be operational.